In the last decade a large body of research has documented a range of structural brain abnormalities in schizophrenic patients, suggesting that schizophrenia can be view as a neurodegenerative disorder. However, it is unclear that any dominant neuropathology defines the disease. This may be because the disease is characterized by several subgroups with diverse etiologic causes. Alternatively, some of the reported neurochemical changes may precede other pathophysiologies. This proposal describes a series of studies, utilizing the techniques of quantitative neurotransmitter autoradiography, histochemistry, and immunocytochemistry to visualize and quantify the neurochemical and neuropathological changes occurring in different clinical populations of schizophrenics. The project will initially focus on documenting changes in the dopaminergic, cholinergic and serotonergic systems and their relationship to neurocytological changes in specified regions of schizophrenic brain tissue. Specifically, to address whether the neuropathological picture is consistent with two clinical populations of schizophrenics. One population having dopamine receptor dysregulation in striatal regions that can be correlated with a predominance of positive symptoms. The other population, with both negative and positive symptoms having, in addition, a neurohemical "isolation" of the hippocampus. Studies are designed to follow-up on the results of the autoradiographic studies by utilizing two approaches to further document and substantiate the neurodegenerative changes in schizophrenia. Comparison to appropriate control tissue, including neuroleptic- treated and non-neuroleptic treated controls will be utilized. Secondly, other neurological disorders will be examined for the similarity or disimilarity to the neurochemical disturbances of schizophrenia. Immunocytochemical studies and Golgi studies will be used to assess the degree and range of neuronal changes in those specific brain regions that are determined by neurotransmitter autoradiography to be most importantly involved in the disorder. The results from these experiments will be of use in identifying potential therapeutic approaches to different clinical populations of schizophrenics, and the development of new approaches for examining the neurochemical and neuropathological basis of other neurological and neuropsychiatric disorders.